GPC2 could be targeted to treat neuroblastoma

View:27 Time:2017-09-12

Scientists studying neuroblastoma have identified the cell-surface protein GPC2 as an oncoprotein and candidate therapeutic target.

Neuroblastoma (NB) is a rare childhood cancer of the nervous system, with an estimated incidence of 1 case per 100,000 children. The cancer is most commonly diagnosed in children under age 5 while rarely seen in adults. Children with high-risk NB usually have a poor prognosis despite intensive treatment. NB accounts for about 12% of cancer-related deaths in children under 15.

For decades, scientists have been studying the pathogenesis of NB. Recent clinical trials and studies have shown that a monoclonal antibody against the tumor-associated disialoganglioside GD2 improved outcome of patients with high-risk NB, in comparison with standard therapy. However, that antibody is highly toxic. It is necessary to develop more effective and less toxic immunotherapies to beat high-risk NB.

Until now, the NB cell-surface proteome has not been well studied. If we can identify cell-surface molecules that correlate with tumor formation or growth and have limited expression on normal cells, we may find new targets for NB therapy.

A team of researchers headed by John Maris at Perelman School of Medicine at the University of Pennsylvania set out to discover cell-surface molecules that could be targeted to develop immunotherapies for NB. To accomplish this, Maris' team developed an RNA-sequencing-based approach, allowing them to identify genes differentially expressed in NBs compared with normal tissues.

They found that a protein, called glypican 2 (GPC2), is highly expressed in most NBs. Earlier studies have implicated the glypican family of proteins in tumorigenesis, and have suggested that glypican proteins are safe and efficacious molecules to target with immunotherapies. Analyzing large datasets of NB, the researchers found that high GPC2 expression correlates with worse overall survival.

Subsequent investigation revealed that GPC2 expression is restricted in normal tissues and is critical for NB cell proliferation. Collectively, these data support that GPC2 is a candidate target for NB treatment. Therefore, drugs that block GPC2 might be able to kill cancer cells without affecting normal cells.

To test the hypothesis, the researchers developed a GPC2-directed antibody-drug conjugate, known as D3-GPC2-PBD. They tested D3-GPC2-PBD in several human NB cell lines and found that it mediated potent cytotoxicity in GPC2-expressing NB cells. Moreover, the cytotoxicity of D3-GPC2-PBD is dose-dependent and correlates with GPC2 cell-surface density.

Finally, D3-GPC2-PBD was tested in a murine model of GPC2-expressing NB. Treatment with D3-GPC2-PBD remarkably prolonged the animals' survival. Besides, the appropriate dose of D3-GPC2-PBD was well tolerated, without obvious adverse effects.

In summary, the cell-surface protein GPC2 is an oncoprotein in NB and can be targeted with antibody-drug conjugates.

The study, titled "Identification of GPC2 as an Oncoprotein and Candidate Immunotherapeutic Target in High-Risk Neuroblastoma," appears in the journal Cancer Cell.